甲基化修饰miR-195/424介导FASN激活PI3K/AKT/NF-κβ信号通路促进骨肉瘤侵袭转

Osteosarcoma tops the list of the malignant primary bone tumors and the pulmonary metastatic disease is the main reason of death. Therefore, to make clear the molecular mechanism of metastasis for improving the curative effect has become one urgent problem to solve. The microRNA regulation plays a very important role in tumor development and process. In our previously studies,we found that decreased expression of miR-195/424 is likely due to methylation regulation in OS cells. In addition,we found that elevated expression of FASN promots OS metastasis via activation of PI3K/AKT/NF-κβ signaling pathway, and up-regulation miR-195/424 could inhibit FASN expression and result in inhibition cell migration and invasion in U2-OS cell.In this,study, we will perform molecular genetics and biology methods to explore that elevated expression of FASN mediated by methylated miR-195/424 promote osteosarcom metastasis via activating PI3K/AKt/NF-κβ signaling pathway in vitro and vivo. If the study was completed successfully, the new therapeutic strategies would be provided for prevention and treating metastasis of OS.

骨肉瘤在青少年和儿童原发恶性骨肿瘤中占据首位，肺部转移是骨肉瘤患者死亡最主要原因，因此阐明骨肉瘤转移分子机制是骨肉瘤防治研究的热点之一。作为表观遗传修饰范畴的microRNA调控在肿瘤的发生发展中起非常重要的作用。我们前期研究发现骨肉瘤细胞中miR-195/424的低表达很可能由于受到高甲基化修饰的调控。我们还证实FASN激活PI3K/AKT/NF-κβ信号通路促进骨肉瘤侵袭转移，并且发现miR-195和miR-424靶向调控FASN抑制骨肉瘤U2-OS细胞体外侵袭、迁移。本研究拟以细胞和裸鼠为研究对象，采用分子遗传学和肿瘤分子生物学方法，在前期研究基础上进一步探讨高甲基化修饰miR-195/424介导FASN基因过表达而激活PI3K/AKT/NF-κβ信号通路促进骨肉瘤转移。本研究的顺利完成将为骨肉瘤侵袭转移的防治提供新的干预环节和治疗策略。

骨肉瘤在青少年和儿童原发恶性骨肿瘤中占据首位，肺部转移是骨肉瘤患者死亡最主要原因，因此阐明骨肉瘤转移分子机制是骨肉瘤防治研究的热点之一。作为表观遗传修饰范畴的microRNA调控在肿瘤的发生发展中起非常重要的作用。我们前期研究发现骨肉瘤细胞中miR-195/424的低表达很可能由于受到高甲基化修饰的调控。我们还证实FASN激活PI3K/AKT/NF-κβ信号通路促进骨肉瘤侵袭转移，并且发现miR-195和miR-424靶向调控FASN抑制骨肉瘤U2-OS细胞体外侵袭、迁移。本研究以骨肉瘤组织及细胞为研究对象，在前期研究基础上进一步探讨高甲基化修饰miR-195/424介导FASN基因过表达而激活PI3K/AKT/NF-κβ信号通路促进骨肉瘤转移。. 研究结果显示，miRNA -195/242在骨肉瘤组织中呈低 表达，并且其启动子区甲基化水平高；FASNS是 miR -195/424 的靶基因，miR-195/424 能负向调控 FASNF而抑制骨肉瘤细胞迁徙和侵袭能力。本研究的顺利完成为骨肉瘤侵袭转移的防治提供了新的干预靶点和治疗思路。